We have developed the first reproducible model of Leishmania infection transmitted by actual sand fly bites, and have anlalyzed the host response in the skin at the site of an infective bite. Prior exposure of mice to the bites of uninfected sand flies conferred powerful protection against L. major that was associated with a strong DTH response, and especially IFNg production, at the site of parasite delivery. The findings imply that the exposure history of individuals to the bites of uninfected sand flies will influence the incidence and severity of leishmanial disease, and they raise the possibility that antigens present within vector saliva might be effective components of an anti-leishmanial vaccine. A plasmid DNA encoding a salivary protein from P. papatasi was found to sensitize mice for DTH response to salivary gland lysates (SGL) and to protect mice against cutaneous leishmaniasis following co-inoculation of parasites and SGL. Leishmania promastigotes synthesize an abundance of phosphoglycans which are either present on the cell surface anchored by PI (lipophosphoglycan, LPG) or secreted as protein-containing glycoconjugates. The relative contributions of different phosphoglycan-containing molecules in Leishmania/sand fly interactions were tested using mutants specifically deficient in either total phosphoglycans or LPG alone. These mutants have revealed dual roles for phosphoglycans as virulence molecules in the sand fly vector: the sereted molecules protect the parasite from proteolytic digestion in the bloodfed midgut, and the surface LPG mediates attachment of the parasite to the gut wall so as to prevent loss of infection during bloodmeal excretion.The hypothesis that the species-specificity of vectorial competence observed in nature is controlled by inter-species polymorphisms in the expression of LPG side-chain oligosaccharides has been strongly supported by an examination of Leishmania / sand fly interactions involving multiple combinations of parasite and vector species. Our most recent studies have involved Phlebotomus sergenti , which is the natural vector of L. tropica and anthroponotic cutaneous leishmaniasis, and has not been previously colonized for use in laboratory based studies. P. sergenti showed a high specificity for L. tropica strains, which were able to develop mature, potentially transmissible infections. The complete loss of infection with L. major and L. donovani correlated with the excretion of the digested bloodmeal. The ability of L. tropica to bind to midgut epithelial cells was mediated by a highly branched LPG structure containing unique terminally exposed arabinose and glucose side-chains.